Nucleic acid amplification is an essential step in most nucleic acid-based detection assays. Accurate detection of nucleic acid biomarkers often relies on the ability to amplify the target nucleic acid in the presence of overwhelming excess (usually 10-fold to 1,000,000-fold) of non-target nucleic acids with sequences similar to the target nucleic acid. In some cases, a non-target nucleic acid differs from a target nucleic acid by as little as one nucleotide (or one nucleotide base pair). Methods of enriching and detecting such rare nucleic acids are often referred to as rare-allele enrichment and rare-allele detection, respectively.